Discovery of dinaciclib (SCH 727965): A potent and selective inhibitor of cyclin-dependent kinases

Article abstract of DOI:10.1021/ml100051d

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability paramete

Full text of DOI:10.1021/ml100051d

pubs.acs.org/acsmedchemlett
Discovery of Dinaciclib (SCH 727965): A Potent and
Selective Inhibitor of Cyclin-Dependent Kinases
†,
†
†
†
†
Kamil Paruch, Michael P. Dwyer, Carmen Alvarez, Courtney Brown, Tin-Yau Chan,
†
†
†
†
†
Ronald J. Doll, Kerry Keertikar, Chad Knutson, Brian McKittrick, Jocelyn Rivera,
†
†
†
†
†
Randall Rossman, Greg Tucker, Thierry Fischmann, Alan Hruza, Vincent Madison,
†
†
†
‡,^
‡
Amin A. Nomeir, Yaolin Wang, Paul Kirschmeier, Emma Lees, David Parry,
‡
‡
‡
‡
Nicole Sgambellone, Wolfgang Seghezzi, Lesley Schultz, Frances Shanahan,
‡
†
†
§
§
Derek Wiswell, Xiaoying Xu, Quiao Zhou, Ray A. James, Vidyadhar M. Paradkar,
§
§
§
,†,#
Haengsoon Park, Laura R. Rokosz, Tara M. Stauffer, and Timothy J. Guzi*
†
‡
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, Merck Research Laboratories,
§
9
3
01 California Avenue, Palo Alto, California 94304, and Ligand Pharmaceuticals (formerly Pharmacopeia),
000 Eastpark Boulevard, Cranbury, New Jersey 08512
ABSTRACT Inhibition of cyclin-dependent kinases (CDKs) has emerged as an
attractive strategy for the development of novel oncology therapeutics. Herein is
described the utilization of an in vivo screening approach with integrated efficacy
and tolerability parameters to identify candidate CDK inhibitors with a suitable
balance of activity and tolerability. This approach has resulted in the identification
of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing
clinical evaluation.
KEYWORDS Cyclin-dependent kinase, oncology therapeutics, SCH 727965
he mammalian cell cycle is a nonredundant process
that integrates extracellular signaling, DNA synthesis,
1
T
and mitosis. Loss of cell cycle control is a hallmark of
all human cancers and is frequently associated with aberrant
2
,3
activation of cyclin-dependent kinases (CDKs). The CDKs
are a well-characterized family of serine/threonine kinases
that regulate cell cycle progression by phosphorylation and
inactivation of the retinoblastoma tumor suppressor gene
product (Rb) throughout late-G1, S, and G2/M phases as well
as playing a role in the G2/M checkpoint and progression
4
-9
through mitosis.
Other members of the CDK family have
also been shown to have functions beyond cell cycle regula-
tion. For example, CDK5 is involved in neuronal function and
10
τ phosphorylation, and CDK7, CDK8, and CDK9 have been
11,12
implicated in transcriptional regulation.
Inhibition of multiple members of the CDK family has
been shown to induce therapeutically desirable phenotypes
such as inhibition of proliferation and apoptosis. For exam-
ple, expression of dominant negative forms of CDK2 and
combinatorial silencing of CDK1 and CDK2 via siRNA gen-
Figure 1. Representative CDK inhibitors in clinical trials.
A number of diverse CDK inhibitors have progressed into
20-23
clinical development (Figure 1).
Flavopiridol has been
1
3-17
erates cell cycle arrest and apoptosis.
Likewise, inhibi-
the most clinically studied CDK inhibitor, and several phase II
trials targeting a variety of indications have been completed.
Thus far, the most significant activity has been reported in
tion of the noncell cycle-related CDKs, CDK7 and CDK9,
depress transcriptional regulation a variety of targets includ-
8
,17
ing several antiapoptotic proteins.
CDK8 modulates B-catenin function, resulting in decreased
Moreover, inhibition of
24
chronic lymphocytic leukemia. Efforts in applying an in
1
8,19
proliferation of colon cancer cells.
Thus, inhibition of the
essential, rate-limiting activities of multiple members of the
CDK family represents an attractive therapeutic strategy for
oncology indications.
Received Date: March 12, 2010
Accepted Date: May 6, 2010
Published on Web Date: May 17, 2010
r 2010 American Chemical Society
204
|
DOI: 10.1021/ml100051d ACS Med. Chem. Lett. 2010, 1, 204–208

pubs.acs.org/acsmedchemlett
a
a
Scheme 1. Preparation of 3-Bromo Derivatives 7-11
Table 1. Optimization in the 5-Position
a
Reagents and conditions: (a) Na, EtOH, diethylmalonate, reflux. (b)
, dimethylaniline, 60 ꢀC. (c) 3-Aminomethyl pyridine, DIPEA,
dioxane. (d) Boc O, DMAP, CH Cl . (e) NBS, CH CN, 0 ꢀC. (f) MCPBA,
CH Cl . (g) HNR , DIPEA, dioxane, 90 ꢀC. (h) KOH, EtOH/H O, 100 ꢀC.
POCl
3
2
2
2
3
2
2
1
R
2
2
Scheme 2. Preparation of 3-Ethyl Aminoalcohol Derivatives 13
a
and 14
a
Dose-response curves were generated from duplicate 8-point
serial dilutions of inhibitory compounds. IC50 values were derived by
nonlinear regression analysis. Thymidine uptake growth inhibition
b
assay in A2780 cells. Percentage inhibitions, relative to vehicle controls,
a
were calculated and plotted on log-linear plots to allow derivation of
Reagents and conditions: (a) Dimethylmalonate, reflux. (b) NaOMe,
2
5,26
IC50 values.
MeOH, reflux. (c) POCl
pyridine N-oxide hydrochloride, NaHCO
NaHCO , NMP, 150 ꢀC.
3
, dimethylaniline, reflux. (d) 3-Aminomethyl
3
, CH CN, reflux. (e) HNR R ,
3
1 2
3
was effective at reducing tumor burden in vivo upon oral
delivery. In an effort to further expand the understanding of
the impact of positional substitution on activity, structure-
activity relationship development was expanded around each
position in the pyrazolo[1,5-a]pyrimidine core.
The preparation of these novel pyrazolo[1,5-a]pyrimidine
CDK inhibitors is outlined in Schemes 1 and 2. The synthesis
of these analogues for the 3-bromo series began with treatment
of 3-aminopyrazole with diethylmalonate under basic condi-
tions followed by chlorination to afford 16. Treatment with
3-aminomethylpyridine followed by Boc protection afforded
intermediate 17. Bromination with NBS followed by oxidation
yielded 18, which was treated with commercially available
amines and deprotected under basic conditions to afford the
vivo screening system to select candidate CDK inhibitors
with the optimal combination of potency, pharmacokinetic,
efficacy, and safety parameters are herein described. This
functional approach allowed rapid differentiation within a
discrete series of compounds as well as benchmarking
against flavopiridol. Ultimately, this approach led to the
identification of SCH 727965, which is currently in phase II
clinical trials.
The utility of the pyrazolo[1,5-a]pyrimidine scaffold as
a basis for the development of novel CDK inhibitors has
previously been described.
2
5,26
From these efforts, com-
pound 6 was identified as a novel CDK inhibitor, which
r 2010 American Chemical Society
205
DOI: 10.1021/ml100051d |ACS Med. Chem. Lett. 2010, 1, 204–208

pubs.acs.org/acsmedchemlett
Table 2. Relative Therapeutic Indices from the in Vivo Screening Paradigm
a
Dose-response curves were generated from duplicate 8-point serial dilutions of inhibitory compounds. IC50 values were derived by nonlinear
b
regression analysis. Thymidine uptake growth inhibition assay in A2780 cells. Percentage inhibitions, relative to vehicle controls, were calculated and
plotted on log-linear plots to allow derivation of IC50 values. Relative therapeutic indices following intraperitoneal (IP) dosing using the in vivo
screening paradigm (MTD = 20% weight loss; MED = 50% inhibition of tumor growth; and QDx7 = once a day dosing for 7 consecutive days).
c
25,26
title compounds 7-11. The corresponding 3-ethyl derivatives
were prepared by cyclization of 3-amino-4-ethyl pyrazole with
dimethylmalonate under basic conditions followed by chlorina-
tion, which afforded 19 (Scheme 2). Treatment of 19 with
by replacement of the aryl functionality at the 5-position
of 6 with N-linked motifs bearing hydroxy substitution
such as 8. Furthermore, with correct positioning of this
functionality, additional improvements in both kinase
activity as well as inhibition of cell growth were observed
in 9-11.
3-(aminomethyl)pyridine N-oxide monohydrochloride under
basic conditions yielded 20 followed by treatment with
known amino alcohols, which afforded title compounds 13
and 14. The preparation of 6 and 12 has been previously
The structural basis for these improvements in activity can
be readily explained by interactions revealed in the X-ray
crystal structure of this series of compounds bound to CDK2
26,27
described.
2
8
As illustrated in Table 1, a key observation made in the
and the CDK2/cyclin A complex. A detailed description of
3
-bromo series was the marked improvement in potency
these findings will be published in due course.
r 2010 American Chemical Society
206
DOI: 10.1021/ml100051d |ACS Med. Chem. Lett. 2010, 1, 204–208

pubs.acs.org/acsmedchemlett
a
Table 3. Exposure Parameters
putative therapeutic index of 1. In contrast, the more highly
potent compound 10 displayed a relative therapeutic index of 5.
Interestingly, simple modification of substitution within this
highly potent series of inhibitor induced significant differences
in relative therapeutic indices. For example, incorporation of a
b
c
compd
AUC (μM h)
C
max (μM)
6
8
1.4
10
6
6
10
3-ethyl substituent as in 13 resulted in an improved overall
1
1
1
1
2
3
4
5
8
profile relative to 10. Conversely, the aminocyclohexyl methyl
alcohol 14 gave a decreased tolerability profile relative to the
piperidine ethanol derivative 13. Notably, these compounds
displayed no significant differences in pharmacokinetic profile
(Table 3 ) or kinase cross-reactivity across a set of diverse
kinases (data not shown). We also benchmarked flavopiridol
15. The ratio of MTD to MED for flavopiridol was <1, indicat-
ing that in this screening system minimal antitumor efficacy
wasattainedbeforethe onsetoftoxicity. Whileramificationsof
these findings are unknown, it is compelling to hypothesize
that a compound such as 13 may have increased potential to
achieve a more robustly active dose range prior to the man-
ifestation of dose-limiting toxicities.
0.8
0.5
N/A
0.8
0.9
N/A
a
Plasma samples from mice were collected at various times after
intraperitoneal administration at 5 mg/kg and analyzed by liquid
chromatography-tandem mass spectrometry. Pharmacokinetic vari-
ables were estimated from the plasma concentration data. The area
b
under the plasma concentration vs time curve (AUC) was calculated
c
using the linear trapezoidal rule.
Cmax values (maximum plasma con-
centration) were taken directly from the plasma concentration-time
26,29
profiles.
The initial goal of these efforts was to identify a novel inhibitor
of CDK1 and CDK2. Because of the high degree of homology
within the CDK family, inhibition of additional CDKs within this
series of compound was also observed (data not shown). Thus,
there exists a realistic likelihood that these small molecule
inhibitors of the CDKs would exert their effects via com-
pound-specific, combinatorial inhibition of multiple members
of the family. This expected multitargeted nature of CDK
inhibitors places a premium on maintaining an adequate
therapeutic index in vivo. In this context, a critical issue in the
development of CDK inhibitors is the relationship between
desirable on-target effects and the onset of off-target tolerability
issues that might adversely affect clinical dose escalation.
Ultimately, a screening system reminiscent of the historical
standard paradigm for cytotoxic drug discovery, which evalu-
ated the tolerability versus activity in vivo, was implemented.
Simply, this in vivo system sought to establish the ratio of
maximally tolerated and minimally effective doses in the
A2780 ovarian carcinoma xenograft model. It was reasoned
that through the application of this screening system, a com-
pound could be identified that might give the best opportunity
to achieve pharmacologically relevantdoses clinically before the
manifestation of toxicity. Hence, the maximally tolerated dose
Several unexpected trends emerged from the utilization of
this screening system. Namely, compounds with very high
levels of potency tended to give improved therapeutic
indices relative to those with lower affinity. Interestingly,
these compounds displayed lower exposure and higher
clearance rates relative to those with lower therapeutic
indices. Taken together, short exposures to highly potent
CDK inhibitors appear to induce long-lasting effects and
have the potential to do so with improved tolerability. This
stands in contrast to efforts in earlier stages of the program,
which had been more focused on chronic exposure to induce
continual CDK inhibition. Additionally, within this series of
compounds, small changes in substitution had a large im-
pact on overall activity and tolerability relationships that
were not predictable from simple in vitro and pharmacoki-
netic profiling.
In summary, a series of pyrazolo[1, 5-a]pyrimidine CDK
inhibitors, which display a range of potency and pharmaco-
kinetic parameters, were identified. Utilizing a functional in
vivo screen, compounds were readily differentiated on the
basis of efficacy versus tolerability profiles even in those
structures with remarkably similar substitution and in vitro
and pharmacokinetic profiles. A key observation arising
from the application of this approach was that highly potent,
rapidly cleared CDK inhibitors appear to give an optimal
balance between efficacy and tolerability. Within com-
pounds of this profile, 13 was selected as a candidate CDK
inhibitor suitable for progression. In-depth evaluation of the
in vitro and in vivo properties further supported the conclu-
sion that 13 had the appropriate qualities for a development
(
MTD) was determined by intraperitoneal administration of
compound to nude mice on a fixed, QDx7 schedule at varying
dose levels. In these experiments, the MTD was defined as the
dose on the QDx7 schedule required to reduce body weight by
20%. In parallel, the minimum effective doses (MEDs) were
established on the same schedule. The MED was defined as the
dose given QDx7 that was associated with >50% tumor growth
inhibition. Pharmacokinetic parameters were also established to
enable calibration of effects on the basis of systemic exposure.
Thus, a series of compounds comprised of diverse structures,
potency, and pharmacokinetic parameters were selected in an
attempt to identify the optimal profile for a CDK inhibitor within
this class of compound.
Through the application of this in vivo screen, clear trends
emerged among compounds of diverse structures and ranges of
potency (Ta ble 2 ). Compound 12, an analogue with improved
in-cell activity relative to the previously described 6, was found
to have an MED of 5 mpk with an MTD of 5 mpk, giving a
2
9
candidate. Compound 13 (SCH 727965) is currently un-
dergoing phase II clinical trials.
SUPPORTING INFORMATION AVAILABLE Experimental
procedures and characterization data for 6-20. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: 1-617-499-3638. E-mail: timothy.guzi@spcorp.com.
r 2010 American Chemical Society
207
DOI: 10.1021/ml100051d |ACS Med. Chem. Lett. 2010, 1, 204–208

pubs.acs.org/acsmedchemlett
Present Addresses: Department of Chemistry, Masaryk Univer-
represses beta-catenin transcription and is antagonized by
both pRB and CDK8. Nature 2008, 455, 552–556.
sity, Kamenice 5, 625 00 Brno, Czech Republic. ^ Novartis Institute for
Biomedical Research, 4560 Horton Street, Emeryville, California 94608-
(20) McInnes, C. Progress in the evaluation of CDK inhibitors
as anti-tumor agents. Drug Discovery Today 2008, 13, 875–881.
(21) DePinto, W.; Chu, X.-J.; Yin, X.; Smith, M.; Packman, K.;
Goelzer, P.; Lovey, A.; Chen, Y.; Qian, H.; Hamid, R.; Xiang, Q.;
Tovar, C.; Blain, R.; Nevisn, T.; Higgins, B.; Luistro, L.; Kolinsky,
K.; Felix, B.; Hussain, S.; Heimbrook, D. In vitro and in vivo
activity of R547: a potent and selective cyclin-dependent
kinase inhibitor currently in phase I clinical trials. Mol. Cancer
Ther. 2006, 5, 2644–2658.
#
2916. Merck Research Laboratories, 320 Bent Street, Cambridge,
Massachusetts 02141.
REFERENCES
(1)
Murray, A. W. Recycling the cell cycle: Cyclins revisited. Cell
004, 116, 221–234.
2
(
(
2)
3)
Sherr, C. J. Cancer cell cycles. Science 1996, 274, 1672–1677.
Hall, M.; Peters, G. Genetic alterations of cyclins, cyclin-
dependent kinases and CDK inhibitors in human cancer.
Adv. Cancer Res. 1996, 68, 67–108.
(
22) Wyatt, P. G.; Woodhead, A. J.; Berdini, V.; Boulstridge, J. A.;
Carr, M. G.; Cross, D. M.; Davis, D. J.; Devine, L. A.; Early, T. R.;
Feltell, R. E.; Lewis, E. J.; McMenamin, R. L.; Navarro, E. F.;
O'Brien, M. A.; O'Reilly, M.; Reule, M.; Saxty, G.; Seavers,
L. C. A.; Smith, D.-M.; Squires, M. S.; Trewartha, G.; Walker,
M. T.; Woolford, A. J.-A. Identification of N-(4-piperidinyl)-
(4)
(5)
(6)
Hunter, T.; Pines, J. Cyclins and cancer II: Cyclin D and CDK
inhibitors come of age. Cell 1994, 79, 573–582.
Ewen, M. E. The cell cycle and the retinoblastoma protein
family. Cancer Metastasis Rev. 1994, 13, 45–66.
Ewen, M. E. Regulation of the cell cycle by the Rb tumor
suppressor family. Results Probl. Cell Differ. 1998, 22, 149–
4
-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide
(
AT7519), a novel cyclin dependent kinase inhibitor using
fragment-based X-ray crystallography and structure based
drug design. J. Med. Chem. 2008, 51, 4986–4999.
1
79.
(
23) Misra, R. N.; Xiao, H.; Kim, K. S.; Lu, S.; Han, W.-C.; Barbosa,
S. A.; Hunt, J. T.; Rawlins, D. B.; Shan, W.; Ahmed, S. Z.; Qian,
L.; Chen, B.-C.; Zhao, R.; Bednarz, M. S.; Kellar, K. A.;
Mulheron, J. G.; Batorsky, R.; Roongta, U.; Kamath, A.;
Marathe, P.; Ranadive, S. A.; Sack, J. S.; Tokarski, J. S.;
Pavletich, N. P.; Lee, F. Y. F.; Webster, K. R.; Kimball, S. D.
N-(Cycloalkylamino)acyl-2-aminothiazole inhibitors of cy-
clin-dependent kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-
oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide
(
7)
8)
Shapiro, G. I. Cyclin-dependent kinase pathways as targets
for cancer treatment. J. Clin. Oncol. 2006, 24, 1770–1783.
Malumbres, M.; Pevarello, P.; Barbacid, M.; Bischoff, J. R. CDK
inhibitors in cancer therapy. What is next?. Trends Pharmacol.
Sci. 2007, 29, 16–21.
(
(9)
Satyanarayana, A; Kaldis, P. Mammalian cell-cycle regulation:
Several Cdks, numerous cyclins and compensatory mechan-
isms. Oncogene 2009, 28, 2925–2939.
(
10) Wei, F. Y.; Tomizawa, K. Cyclin-dependent kinase 5 (Cdk5): A
potential therapeutic target for the treatment of neurodegen-
erative diseases and diabetes mellitus. Mini Rev. Med. Chem.
(
BMS-387032), a highly efficacious and selective antitumor
agent. J. Med. Chem. 2004, 47, 1719–1728.
(
24) Christian, B. A.; Grever, M. R.; Byrd, J. C.; Lin, T. S. Flavopiridol
in the treatment of chronic lymphocytic leukemia. Curr. Opin.
Oncol. 2007, 19, 573–578.
2
007, 7, 1070–1074.
(
11) Bregman, D. B.; Pestell, R. G.; Kidd, V. J. Cell cycle regulation
and RNA polymerase II. Front. Biosci. 2000, 5, D244–D257.
12) Oelgeschlager, T. Regulation of RNA polymerase II activity by
CTD phosphorylation and cell cycle control. J. Cell Physiol.
(
25) Dwyer, M. P.; Paruch, P.; Alvarez, C.; Doll, R. J.; Keertikar, K.;
Duca, J.; Fischmann, T. O.; Hruza, A.; Madison, V.; Lees, E.;
Parry, D.; Seghezzi, W.; Sgambellone, N.; Shanahan, F.;
Wiswell, D.; Guzi, T. J. Versatile templates for the develop-
ment of novel kinase inhibitors: discovery of novel CDK
inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 6216–6219.
(
2
002, 190, 160–169.
(13) van den Heuvel, S.; Harlow, E. Distinct roles for cyclin-
dependent kinases in cell cycle control. Science 1993, 262,
2
050–2054.
(
14) Hu, B.; Mitra, J.; van den Heuvel, S.; Enders, G. H. S and G2
phase roles for Cdk2 revealed by inducible expression of a
dominant-negative mutant in human cells. Mol. Cell. Biol.
(26) Paruch, P.; Dwyer, M. P.; Alvarez, C.; Brown, C.; Chan, T.-Y.;
Doll, R. J.; Keertikar, K.; Knutson, C.; McKittrick, B.; Rivera, J.;
Rossman, R.; Tucker, G.; Fischmann, T. O.; Hruza, A.; Madison,
V.; Nomeir, A.; Wang, Y.; Lees, E.; Parry, D.; Sgambellone, N.;
Seghezzi, W.; Schultz, L.; Shanahan, F.; Wiswell, D.; Xu, X.;
Zho, Q.; James, R. A.; Paradkar, V.; Park, H.; Roskosz, L.;
Stauffer, T.; Guzi, T. J. Pyrazolo[1,5-a]pyrimidines as orally
available inhibitors of cyclin-dependent kinase 2. Biorg. Med.
Chem. Lett. 2007, 17, 6220–6223.
2
001, 21, 2755–2766.
(
15) L'Italien, L.; Tanudji, M.; Russell, L.; Schebye, X. M. Unmask-
ing the redundancy between Cdk1 and Cdk2 at G2 phase in
human cancer cell lines. Cell Cycle 2006, 5, 984–993.
16) Webster, K. R.; Kimball, D. Novel drugs targeting the cell
cycle. Emerging Drugs 2000, 5, 45–59.
17) Cai, D.; Latham, V. M., Jr.; Zhang, X.; Shapiro, G. I. Combined
depletion of cell cycle and transcriptional cyclin-dependent
kinase activities induces apoptosis in cancer cells. Cancer Res.
(
(
(27) Full experimental details for the preparation of compounds 6
and 12 can be found in the Supporting Information.
(28) Fischmann, T. O.; Hruza, A.; Duca, J. S.; Ramanathan, L.;
Mayhood, T.; Windsor, W. T.; Le, H. V.; Guzi, T. J.; Dwyer, M. P.;
Paruch, K.; Doll, R. J.; Lees, E.; Parry, D; Seghezzi, W.;
Madison, V. Structure-guided discovery of cyclin-dependent
kinase inhibitors. Biopolymers 2008, 89, 372–379.
(29) Parry, D.; Guzi, T.; Shanahan, F.; Davis, N.; Prabhavalkar, D.;
Wiswell, D.; Seghezzi, W.; Paruch, K.; Dwyer, M. P.; Doll, R.;
Nomeir, A.; Windsor, W.; Fischmann, T.; Wang, Y.; Oft, M.;
Chen, T.; Kirschmeier, P.; Lees, E. SCH 727965, a novel and
potent cyclin-dependent kinase inhibitor. Mol. Cancer Ther.
Submitted for publication.
2
006, 66, 9270–9280.
(
18) Firestein, R.; Bass, A. J.; Kim, S. Y.; Dunn, I. F.; Silver, S. J.;
Guney, I.; Freed, E.; Ligon, A. H.; Vena, N.; Ogino, S.; Chheda,
M. G.; Tamayo, P.; Finn, S.; Shrestha, Y.; Boehm, J. S.; Jain, S.;
Bojarski, E.; Mermel, C.; Barretina, J.; Chan, J. A.; Baselga, J.;
Tabernero, J.; Root, D. E.; Fuchs, C. S.; Loda, M.; Shivdasani,
R. A.; Meyerson, M.; Hahn, W. C. CDK8 is a colorectal cancer
oncogene that regulates beta-catenin activity. Nature 2008,
455, 547–551.
(
19) Morris, E. J.; Ji, J.-Y.; Yang, F.; Di Stefano, L.; Herr, A.; Moon,
N.-S.; Kwon, E.-J.; Haigis, K. M.; Naar, A. M.; Dyson, N. J. E2F1
r 2010 American Chemical Society
208
DOI: 10.1021/ml100051d |ACS Med. Chem. Lett. 2010, 1, 204–208